During the 6-year study period (1997–2003), we enrolled 1856 patients with lung cancer, of whom 1585 were matched with unrelated controls and 1053 had full sibling controls. The α1AT allele types were tested in 1443 patients, 797 unrelated controls, and 902 full siblings in the order the samples were received. lists the basic demographic characteristics of the patients and controls. For these variables, patients with lung cancer who were tested for α1AT allele type were very similar to those who were not (no statistically significant difference, P=.31-.96); likewise, α1AT-typed controls were very similar to all controls enrolled in our study.
Basic Description of Study Participants
COMPARISON BETWEEN PATIENTS AND UNRELATED CONTROLS
We applied multiple logistic regression models to examine the effects of tobacco exposure history, COPD, and α1ATD carrier state on lung cancer risk. First, we modeled 1585 case-control pairs ( [model 1]) without the α1ATD variable. This model demonstrated the relative importance of COPD as a risk factor and different levels of tobacco smoke exposure, including ETS alone and light, moderate, and heavy smokers. Individuals with COPD had a greater than 6-fold higher lung cancer risk, and smokers were at a 2- to 9-fold higher risk than never smokers, depending on smoking intensity. Although ETS did not significantly increase lung cancer risk (OR, 1.2), a trend test of a 5-level cigarette smoking exposure intensity (never smokers with no ETS, never smokers with ETS, and light, moderate, and heavy smokers) was significant (P<.01).
Comparison of Patients and Unrelated Controls by Multiple Logistic Regression Analysis
We then built a model including the α1ATD allele types ( [model 2]). The overall α1ATD carrier rate among 1443 patients with lung cancer was 13.4%. The carrier rate in 797 unrelated controls was 7.8% (P<.001). The uneven proportion genotyped (78%, 50%, and 75% of patients, unrelated controls, and sibling controls, respectively) was driven by the natural process of subject enrollment. No significant difference between tested and untested groups was found.
The α1ATD alleles included mainly S (6.7%), Z (3.2%), and other rare ones (I, P, V, and null type making up collectively 2.6% of the allele type distribution in all study participants). Individuals carrying 1 or 2 deficient alleles were all considered as high-risk allele carriers and more than 90% were heterozygous (including SZ) or carriers. These carriers were at a 70% higher risk of developing lung cancer than the noncarriers. Among nonsmokers, ETS was associated with a 2-fold increase in lung cancer independent of α1ATD carrier status. Compared with model 1, the risk for chronic bronchitis or emphysema was similar, whereas the risks associated with the different levels of smoking intensity were approximately doubled.
To further test whether the association between lung cancer risk and α1ATD carrier status varied by history of tobacco smoke exposure and/or COPD, histologic type of lung cancer, and family history of lung cancer and/or other malignancies, we conducted stratified analyses on our case-unrelated control data set.
Among never smokers, we found that α1ATD allele carriers were at a 2.2-fold risk for lung cancer compared with noncarriers after adjusting for age, sex, and history of unspecified COPD. In addition, the increased risk for never smokers with ETS was 2.0-fold (95% confidence interval [CI], 1.3–3.0). depicts the risk estimates for lung cancer (OR) stratified by smoking intensity. Among moderate to heavy smokers (≥20 pack-years), the α1ATD allele–associated lung cancer risk was estimated at 2.3-fold, whereas among light smokers (<20 pack-years), the α1ATD allele–associated lung cancer risk was 2.0-fold (not significant [95% CI, 0.9–4.3]). Having a history of COPD increases lung cancer risk significantly for all 3 groups of smokers (from 2.5- to 5.9-fold), with the largest effect on never smokers (OR, 5.9; 95% CI, 2.7–12.8).
Adjusted odds ratio of risk factors by smoking intensity. α1ATD indicates alpha1-antitrypsin deficiency; COPD, chronic obstructive pulmonary disease; and ETS, environmental tobacco smoke. Error bars indicate 95% confidence intervals.
TUMOR HISTOLOGIC FEATURES
Stratified analysis by selected histologic groups showed varying odds ratios of specific lung cancer risk associated with α1ATD allele carriers (), from not significant in small cell lung cancer (OR, 1.4; 95% CI, 0.6–3.1) to significant in adenocarcinoma, particularly bronchioalveolar carcinoma (OR, 2.0; 95% CI, 1.1–3.8), and also significant in squamous cell carcinoma (OR, 2.5; 95% CI, 1.2–5.3). While the effect of COPD on various types of lung cancer was relatively constant with the exception of small cell carcinoma, the effect of smoking history was dramatically different across histologic groups (OR, 2.0–12.1), with the strongest effect on squamous cell carcinoma (OR, 12.1; 95% CI, 4.9–30.2).
Figure 3 Adjusted odds ratios (95% confidence intervals) of risk factors by cell types of lung cancer. α1ATD indicates alpha1-antitrypsin deficiency; COPD, chronic obstructive pulmonary disease; AD, adenocarcinoma; BAC, bronchioalveolar carcinoma; SQCLC, (more ...)
FAMILY HISTORY OF CANCER
Patients with a family history of lung cancer or other cancers in their first-degree relatives had a similar α1ATD carrier rate to those without such a family history, all significantly higher than the controls. This finding suggests that increased lung cancer risk among α1ATD carriers is independent of a family history of cancer.
COMPARISON BETWEEN PATIENTS AND UNAFFECTED SIBLINGS
Consistent with the results of patient–unrelated-control comparisons, α1ATD allele carriers were at a 2-fold higher lung cancer risk than noncarriers (OR, 2.2; 95% CI, 1.6–2.9) in univariate analysis, and COPD was a very strong risk factor for lung cancer (OR, 5.7; 95% CI, 4.4–7.3). When adding COPD to the model that included α1ATD and the other covariates (), we found that the odds ratio for an increased lung cancer risk in α1ATD carriers was 2.0 (95% CI, 1.4–2.7), supporting an independent role of α1ATD state in lung cancer development. Noted is the lack of difference or trend among the 3 odds ratios for COPD subgroups (chronic bronchitis only, emphysema only, and both); this could reflect the low occurrence of COPD in unaffected siblings and therefore the unstable risk estimates.
Comparison of Patients and Sibling Controlsa
POPULATION ATTRIBUTABLE RISK ESTIMATION
We estimated the EAR based on our multivariable models. The EAR for α1ATD carriers, COPD, and ETS among never smokers was 12%, 10%, and 41%, respectively. Among heavy smokers, the EAR for α1ATD carriers was 11%, and for COPD it was 12%, adjusting for pack-years of cigarettes smoked. Therefore, the α1ATD allele type might explain 11% to 12% of lung cancer occurrence in our population, which was predominantly from the US Midwest, represented by the majority of our study subjects.